There is increasingly convincing evidence that radiotherapy outcomes for many patients with localized prostate cancer can be improved by delivering higher cumulative radiation doses to the prostate. These dose escalation regimens employ relatively small fraction sizes of 1.8-2.0 Gy, based upon evidence that late responding normal tissues, with their lower alpha/beta ratios, are spared relative to most tumors with their higher alpha/beta ratios. For prostate tumors, as many as 38 to 45 or more treatments have been required to deliver escalated doses of 74 Gy or higher using these small fraction sizes. Contrary to these expectations, however, recent analyses of clinical prostate cancer radioresponse data have indicated a low alpha/beta ratio for prostate cancer on the order of 1.5 Gy, not the typical ratio of 8 Gy or higher expected for most tumors. This value is lower than the value of 3 typically ascribed to the adjacent organs at risk, bladder and rectum, probably because prostate tumors have unusually low proliferation rates. What is implied is an unusual opportunity in prostate cancer to improve the therapeutic ratio radiobiologically by treating with fewer but larger fractions of radiation - in other words, with hypofractionation. With a better therapeutic ratio, hypofractionation should lead to higher rates of tumor control without increase in late toxicity. This application: 1) reviews the work of ourselves and others providing evidence for the high relative sensitivity of prostate tumors to large radiation fraction sizes; 2) develops and describes a multi-institutional phase l/ll clinical trial that will test in 250 patients the hypotheses that prostate hypofractionation is both feasible and efficacious and 3) describes an accompanying correlative study that examines the relationship between the status of certain biomarkers and clinical outcome after radiation hypofractionation. This proposal combines the efforts of four institutions and four sets of investigators who collectively have comprehensive experience with the radiobiological modeling, the clinical application of radiation hypofractionation and state-of-the-art prostate cancer radiotherapy for prostate cancer. It is hoped that outcomes from this study will demonstrate that hypofractionated radiotherapy is safe and is at least as efficacious as aggressive, conventional-fraction-size dose escalation. If proven feasible, the fewer treatment fractions involved would also result in significant economic and resource utilization advantages and would reduce the patient burden associated with the 38 or more treatments typically required in many current, dose escalation regimens.